| Budget Amount *help |
¥3,910,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Research Abstract |
To overcome various immune diseases induced by disruption of type1/type2 immune balance, we have established Th1- or Th2-dependent immune diseases models. In the present project, we established allergic airway inflammation mouse models by adoptive transfer of antigen-specific Th1 or Th2 cells followed by the antigen inhalation and investigated precise cellular regulation and molecular mechanisms in the pathogenesis. In the present models, transfer of Th1 cells induced fatal airway hyperresponsiveness (AHR) associated with severe neutrophilia, whereas the cased of Th2 cells caused eosinophilia in the lung. Compared to the Th2-transferred model, mRNA expression levels of MUC5AC and Gob5, related to mucus hypersecretion in airway epithelium, were extremely lower in the Th1 -transferred model. Thus, it was demonstrated that the Th1-induced AHR was independent on such mucus hypersecretion, which was essential for elevation of AHR in Th2-mediated asthma. In the Th2-transferred model, we foun
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d that in vivo injection of TLR9 ligand, CpG remarkably suppressed the symptoms by blocking of Th2-cell migration into lung. To investigate the mechanism, we used IFN-γ knockout mice and neutralizing antibodies against type I cytokines such as IFN-α, β, and IL-12. As the results, IFN-α, β, and IL-12, but not IFN-γ, were required for the inhibitory effect of CpG on Th2-cell migration. These findings were highly valued for elucidation of the suppression mechanism mediated by down-regulation of Th2-cell migration into lung even at effector phase, suggesting that CpG would be expected as a tool for clinical application in Th2-dependent asthma.
Furthermore, we evaluated inhibitory effects of lactic acid bacterium (LAB), which easily activate type1 immunity, on Th2-dependent asthma. As the results, it was suggested that oral intake of LAB may have preventative effects on the allergic inflammation at induction phase rather than therapeutic effects at effector phase. The present findings will contribute to elucidation of the pathogenesis and development of the proper regulation in allergic airway inflammation. Less
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